Two major hurdles in developing effective vaccines for chronic infections such as HIV, TB and malaria are the lack of knowledge of the critical factors for maintenance of protective immunity, and the lack of a measurable cell type that correlates with protection. To address these gaps in our knowledge, we propose to identify the protective memory T cell subsets in chronic malaria infection and define the mechanisms that they use to survive and maintain protective cytokine production. Our preliminary data demonstrate that malaria- specific T cells differentiate into effector memory cells (Tem), which contribute to protection best if they are exposed to chronic infection. Chronic infection also enhances their Th1 cytokine production (IFN3+), correlating with this protection. Therefore, our central hypothesis is that Tem subsets maintain a protective cytokine program like committed Th1 cells that is maintained by the inflammation associated with chronic infection. The goals of this proposal are therefore to determine which CD4+ memory T cell subsets are protective and survive and which help B cells (T follicular helper, Tfh) or remain committed to the Th1 phenotype. These goals will be achieved by the completion of the following specific aims: 1) To determine protection, survival and effector function (Th1, Tfh) of CD4+ effector memory T cell subsets, and 2) To determine subsets producing IFN3 and their degree of Th1 commitment.
The first aim will define protective memory T cell subsets and the factors required for their maintenance and will be accomplished by in vivo protection, survival and cytokine production assays already established as feasible in the applicant's hands, using modern in vivo immunological techniques and multi-parameter flow cytometry.
The second aim i s firstly to test the in vitro stability of the Th1 cytokine profile of malaria-specific memory cells, using the same techniques I used in my dissertation work, and secondly;to study the indicative pattern of cytokines, cytokine receptors, transcription and chromatin tatistics factors to define mechanisms utilized by Th1 memory cells for maintenance of their effector function in chronic infection. The outcomes of these two aims will allow us to define stimuli used by protective memory CD4+ T cells to survive and the mechanisms to remain protective in chronic infection. Providing knowledge including both novel stimuli to include for a successful vaccination protocol and a memory T cell- type that correlates with protection. The approach is innovative because we have a novel malaria-specific T cell transgenic system, an accurate murine malaria model, using Plasmodium chabaudi;and also because the proposal focuses on effector memory T cells, though others have disregarded them in favor of central memory cells, in spite of evidence of better protection by Tem. This approach to vaccination is supported by evidence that generating and maintaining effector memory cells by vaccination is feasible. The proposed research is significant because the outcomes are directly applicable to malaria, HIV and TB vaccination trials and may speed the search for a protective vaccine to malaria, one of the most lethal infections of mankind.

Public Health Relevance

Malaria is a major mosquito-borne parasite pathogen affecting the lives of 5- 10% of the world population, and killing 1-2 million per year worldwide. Infection rates are on the rise due to increased drug and pesticide resistance, but development of vaccines is entering a hopeful phase, only marred by low rates and short terms of protection. The studies proposed in this application will advance our understanding of immunity to malaria and provide important insights for the development of vaccines designed to promote long-lived cellular immunity to malaria and other chronic infections like HIV and Tuberculosis